Neurons and other excitable cells use ion channel proteins to generate electrical and chemical signals. Understanding the structure and functional mechanisms of voltage-activated ion channels is of particular significance because these proteins generate nerve impulses, providing a critical solution to the biological problem of signaling rapidly over long distances. A mechanistic understanding of these proteins is also of medical significance because they are involved in many disease, and are widely targeted by therapeutic drugs. Recent X-ray structures of voltage-activated potassium (Kv) channels have led to new ideas about how interactions between voltage-activated ion channels and the surrounding membrane are crucial for function of these channels, a theme that we be exploring in our studies. We propose to use several approaches to explore the structural basis of the interaction of toxins, small molecules and lipids with S1-S4 domains from voltage-activated ion channels embedded in membrane environments. Although much of this aim will focus on S1-S4 domains in Kv channels, within this context we also seek to extend our studies to include transient receptor potential (TRP) channels, a fascinating family of sensory channels with diverse functions, ranging from sensing temperature and pain, to detecting natural products. We will attempt to define S1-S4 domains in TRP channels, and explore the interactions of their amphipathic activators within the membrane.